The present invention relates to novel, non-peptidic compounds which exhibit a selective agonistic action on the bombesin receptor of subtype 3 (BRS-3), and to pharmaceutical preparations containing these compounds and also processes for the preparation of these compounds.
Bombesin (Bn) is a peptide consisting of 14 amino acids which was originally isolated from amphibians. The two peptides neuromedin B (NMB) and the “gastrin-releasing peptide” (GRP) which have been identified in mammals represent structurally similar peptides. These bombesin-like peptides are the naturally endogenous ligands of the corresponding bombesin receptors, the “neuromedin B receptor” (NMB-R, BB1) and the “gastrin-releasing peptide receptor” (GRP-R, BB2). The bombesin receptors belong to the group of the G-coupled receptors with 7 transmembrane domains.
Due to the homology of its amino acid sequence, the bombesin receptor of subtype 3 (BRS-3 or BB3) is assigned to this family of bombesin receptors [cf. Fathi et al. (1993) J. Biol. Chem. 268:5979-84; cited below as “Fathi et al.”]. The natural ligand of BRS-3 is hitherto unknown. The expression of BRS-3 was demonstrated in various regions of the brain [cf. Yamada et al. (1999) Physiol. Behav. 66:863-7], in secondary spermatocytes [cf. Fathi et al.], in pancreatic islet cells [cf. Fleischmann et al. (2000) Lab. Invest. 80:1807-17] and in the uterine tissue of pregnant animals [cf. Gorbulev et al. (1992) Eur. J. Biochem. 208:405-10]. Furthermore, BRS-3 was identified in different human cancer cell lines (e.g. lung [cf. Fathi et al.], breast [cf. Gorbulev et al. (1994) FEBS Lett. 340:260-4], prostate [cf. Sun et al. (2000) Prostate. 42:295-303] or ovary [cf. Sun et al. (2000) Regul. Pept. 90:77-84]).
Genetically altered mice in which the BRS-3 gene had been knocked out (“BRS-3 Knockout Mice”) exhibited a clinical picture which comprised obesity, hyperphagia and also hypertension and diabetes [cf. Okhi-Hamazaki et al. (1997) Nature 390:165-9]. According to this, BRS-3 appears to be an essential participant in the regulation of glucose metabolism and lipometabolism, in maintaining the energy status and in controlling blood pressure, and also in influencing eating behaviour. It can therefore be assumed of BRS-3 agonistic compounds that they are suitable in particular for the prophylaxis and/or treatment of pathological conditions such as obesity (=adiposity), diabetes, hyperinsulinism, cardiovascular diseases, eating disorders (hyperphagia, anorexia, bulimia) and/or metabolic syndrome (=syndrome X). Syndrome X manifests itself above all by Type II diabetes mellitus and/or reduced glucose tolerance, arterial hypertension, lipometabolism disorders, obesity and also coronary heart disease.
Furthermore, it is known that the activation of BRS-3 can have a neuro-protective action [cf. WO 01/68120]. Also BRS-3 appears to be connected to taste perception [cf. Yamada et al. (1999) Physiol. Behav. 66:863-7], influencing of social behaviour [cf. Yamada et al. (2000) Physiol. Behav. 68:555-61] and certain emotional behaviors [cf. Yamada et al. (2002) Mol. Psychiatry. 7:113-7]. It can therefore likewise be assumed that BRS-3-modulatory compounds may be suitable for the prophylaxis and/or treatment of psychic clinical pictures such as depression or anxiety states, taste perception disorders and/or degenerative diseases of the central nervous system, for example Parkinson's or Alzheimer's.
Some synthetic peptidic ligands are already known which bind with a certain affinity to BRS-3 and exert an agonistic action thereon, namely the BRS-3 selective octapeptide [D-Phe6, Phe13]Bn(6-13) propylamide [cf. Wu et al. (1996) Mol. Pharmacol. 50:1355-63] and also the less-selective nonapeptide [D-Tyr6, β-Ala11, Phe13, Nle14]Bn(6-14) [cf. Mantey et al. (1997) J. Biol. Chem. 272:26062-71] and its derivatives [cf. Pradhan et al. (1998) J. Pharmacol. 343:275-87; Mantey et al. (2001) J. Biol. Chem. 276:9219-29].
Low-molecular, non-peptidic bombesin-analogous compounds are furthermore already known from WO 98/07718, but these are selective antagonists of the other two subtypes of the bombesin receptor family (NMB-R and GRP-R). Low-molecular, non-peptidic compounds which have a selective agonistic effect with high affinity to BRS-3 on the other hand have not been described hitherto.